Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials

Figures & data

Figure 1. Overview of the Japanese clinical development program and the studies included in this review. SB single blind; SAD single ascending dose; PBO placebo; ETN etanercept; DB double blind; RA rheumatoid arthritis; BIW twice weekly; OL open-label; MTX methotrexate; QW once weekly.

Table 1. Summary of clinical studies.

		Registrational		Extension		ETN QW dose regimen
Study	Pharmacokinetic	Bridging	Radiographic	Long-term	Self-injection	ETN 50-mg QW switching	ETN 25-mg QW
Participants	Healthy male	Active RA who have inadequate response to at least one conventional synthetic DMARD (DMARD-IR)	Active RA who have inadequate response to at least one conventional synthetic DMARD (DMARD-IR)	Patient who participated in bridging study	Patients who participated in long-term study	Patients with stable disease activity who received ETN 25 mg BIW for 6 mo in PMS	Active RA who have inadequate response to at least one conventional synthetic DMARD (DMARD-IR)
n	30	147	550	135	58	42	95
Design	DBT, SAD	DBT	DBT	Open	Open	Open-dose switching	DBT
No. of SJC and TJC at BL	NA	SJC: ≥ 6 TJC: ≥ 12	SJC:≥ 6 TJC: ≥ 6	NA	NA	NA	SJC: ≥ 6 TJC: ≥ 6
Treatment groups	Placebo SC ETN 10 mg SC ETN 25 mg SC ETN 50 mg SC	Placebo ETN 10 mg BIW SC ETN 25 mg BIW SC	MTX (≤ 8 mg/wk) oral ETN 10-mg BIW SC ETN 25-mg BIW SC	ETN 25 mg BIW SC	ETN 25-mg BIW SC	ETN 25-mg BIW SC switch to ETN 50 mg QW SC	ETN 10-mg BIW SC ETN 25-mg QW SC
Treatment duration	Single dose	12 wk	52 wk	Until approval (max 182 wk)	Until approval (max 132 wk)	12 wk (ETN 25 mg BIW for 4 wk followed by ETN 50 mg QW for 8 wk)	12 wk
Primary efficacy assessment	NA	ACR20 response rate at wk 12	Change of mTSS from baseline at wk 52	ACR response rates over time	ACR response rates over time	Difference of change from BL for DAS28 ESR at wk 4 and 12	Difference of change from BL for DAS28 ESR between 10 mg BIW and 25 mg QW at wk 12
Safety assessment	Medical history, monitoring of AEs, vital signs (in the sitting position), body weight, height, complete physical examination, CXR, 12-lead ECG, HBsAg and Ab to HCV, blood chemistry, hematology, and urinalysis, and serum and urine HCG for women of childbearing potential (excluding PK study). Particular attention given to infections.
PK sampling	Intensive	Trough	Trough	NA	NA	Intensive (sub-study, n = 18)	Trough
Immunogenicity	NA	Anti-ETN Ab Neutralizing Ab	NA	Anti-ETN Ab Neutralizing Ab	Anti-ETN Ab Neutralizing Ab	NA	NA

PK pharmacokinetic; ETN etanercept; QW once weekly; DMARD-IR patients with active RA who had inadequate response to ≥ 1 disease modifying anti-rheumatic drug; BIW twice weekly; PMS post-marketing surveillance; DBT double-blind trial; SAD single ascending dose; SJC swollen joint count; TJC tender joint count; BL baseline; NA not applicable; SC subcutaneous; MTX methotrexate; ACR American College of Rheumatology; mTSS modified total Sharp score; DAS28 ESR Disease Activity Score in 28 joints; AE adverse event; CXR chest x-ray; ECG electrocardiogram; HBsA hepatitis B surface antigen; Ab antibody; HCV hepatitis C virus; HCG human chorionic gonadotropin.

Table 2. Baseline demographics and disease characteristics in the registrational and ETN QW dosing regimen studies.

	Registrational		ETN QW dosing regimen
	Bridging N = 147	Radiographic N = 550	50-mg QW switching N = 42	25-mg QW N = 95
Age, y	52.6 (11.6)	51.2 (11.7)	53.1 (13.2)	54.7 (10.5)
Sex, n (%)
Male	21 (14.3)	111 (20.2)	7 (16.7)	10 (10.5)
Female	126 (85.7)	439 (79.8)	35 (83.3)	85 (89.5)
Disease duration, y	11.0 (9.3)	3.0 (2.7)	10.9 (8.2)	8.3 (6.9)
RF positive, n (%)	136 (92.5)	422 (76.7)	–	–
CRP, mg/dL	4.9 (3.3)	2.2 (2.6)	0.2 (0.4)	3.4 (2.8)
ESR, mm/hr	72.7 (30.1)	42.7 (28.4)	24.0 (16.8)	64.8 (32.3)
DAS28 ESR	7.1 (0.9)	5.8 (1.1)	3.2 (0.4)	6.4 (1.0)
Tender joint count	28.0 (13.4)	10.4 (6.1)^a	1.9 (2.1)^a	11.6 (6.6)^a
Swollen joint count	22.4 (11.2)	9.5 (5.3)^a	1.7 (2.1)^a	10.9 (5.8)^a
Physician global assessment^b	67.3 (17.1)	6.3 (1.9)	2.1 (1.1)	6.7 (2.0)
Patient global assessment^b	67.8 (18.1)	6.0 (2.2)	2.9 (1.4)	6.7 (2.1)
Pain VAS score	65.3 (17.6)	54.0 (22.8)	21.5 (13.6)	60.2 (21.3)
HAQ-DI	1.7 (0.6)	1.1 (0.7)	0.6 (0.6)	1.4 (0.6)
Duration of morning stiffness, min	4.2 (6.6)	210.6 (328.9)	11.1 (17.0)	154.2 (191.1)
mTSS	–	43.4 (42.3)	–	–
Annualized mTSS progression rate	–	28.2 (40.5)	–	–
Erosion score	–	25.7 (24.1)	–	–
Joint space narrowing score	–	17.7 (20.0)	–	–
Prior MTX use	127 (86.4)	352 (64.0)	29 (69.0)	60 (63.2)

ETN etanercept; QW once weekly; RF rheumatoid factor; CRP C-reactive protein; ESR, erythrocyte sedimentation rate; DAS28 ESR Disease Activity Score in 28 joints; VAS visual analogue scale; HAQ-DI Health Assessment Questionnaire disability index; mTSS, modified total Sharp score.

Values are mean (standard deviation) unless otherwise noted.

^aBased on 28 joints; ^bThe bridging study used a 100-mm scale whereas the radiographic, 50-mg QW switching, and 25 QW studies used a 10-mm scale.

Figure 2. American College of Rheumatology (ACR) 20 and ACR70 responses over time. (a) Bridging (etancercept [ETN] 10 mg twice weekly [BIW], ETN 25-mg BIW, placebo [PBO]), long-term, and self-injection studies. (b) Radiographic study. (c) ETN 25 mg once weekly (QW) study. *P < 0.001 for both ETN 25-mg BIW and ETN 10-mg BIW versus PBO; **P = 0.027 for ETN 10-mg BIW versus PBO. ^†P ≤ 0.0001 for ETN 10-mg BIW or ETN 25-mg BIW versus methotrexate (MTX) ≤ 8 mg/w at all points unless otherwise noted; ^††P ≤ 0.01 for ETN 10-mg BIW versus MTX ≤ 8 mg/w and ETN 25-mg BIW versus MTX ≤ 8 mg/w; ^†††P ≤ 0.05 for ETN 10 mg BIW versus MTX ≤ 8 mg/w and ETN 25-mg BIW versus MTX ≤ 8 mg/w; P = not significant for ETN 10-mg BIW ACR70 versus MTX ≤ 8 mg/w at Week 8.

Figure 3. Mean changes in Disease Activity Index for 28 joints (DAS28 ESR) scores over time. (a) Bridging (etancercept [ETN] 10-mg twice weekly (BIW), ETN 25-mg BIW, placebo [PBO]), long-term, and self-injection studies. (b) Radiographic study. (c) ETN 25-mg once weekly (QW) study. *P < 0.001 for both ETN 25-mg BIW and ETN 10-mg BIW versus PBO. ^†P ≤ 0.0001 for ETN 10-mg BIW or ETN 25-mg BIW versus methotrexate (MTX) ≤ 8 mg/w.

Figure 4. Mean change in modified total Sharp score (mTSS) from baseline over time in the radiographic. *P < 0.0001 for etanercept (ETN) 10-mg twice weekly (BIW) and ETN 25-mg BIW versus methotrexate (MTX) ≤ 8 mg/w; P = not significant for ETN 10-mg BIW versus ETN 25-mg BIW and any time point. Error bars represent standard error. Adapted with permission from Takeuchi T, et al. Mod Rheumatol 23(4), 623–633, 2013 [12].

Figure 5. Time to discontinuation during the radiographic and extension studies. (a) Radiographic study (52 weeks). (b) Long-term study (182 weeks). (c) Self-injection study (132 weeks). ETN etanercept; BIW twice weekly; AE adverse event; LOE loss of efficacy.

Table 3. Adverse events: (a) Overall adverse events; (b) Common adverse events; (c) Common infections. (a) Overall adverse events (AEs).

	Pooled (bridging, long-term, and self- injection) studies^a	Radiographic study^a
Treatment group No. of patients Estimate exposure	ETN 25-mg BIW^c N = 147 Total exposure = 375.4 pt-y	ETN 10-mg BIW n = 192 Total exposure = 168.3 pt-y	ETN 25-mg BIW n = 182 Total exposure = 160.3 pt-y	MTX ≤ 8 mg/wk n = 176 Total exposure = 141.6 pt-y
Any TEAE,^bn/N (%)	143 (97.3)	150 (78.1)	128 (70.3)	125 (71.0)
Death, n/N (%)	1	0	0	0
SAE,^bn (%)	45 (30.6)	8 (4.2)	11 (6.0)	10 (5.7)
Discontinuation owing to AE, n (%)	24 (16.3)	14 (7.3)	17 (9.3)	8 (4.5)
Overall treatment-emergent infections, n/N (%)	124 (84.4)	106 (55.2)	102 (56.0)	92 (52.3)
Serious infections, n/N (%)	21 (14.3)	2 (1.0)	0	1 (0.6)
Discontinuation owing to infection, n/N (%)	17 (11.6)	4 (2.1)	3 (1.6)	1 (0.6)
Opportunistic infections, n/N (%)	0	0	0	0
TB, n/N (%), [events/100 pt-y]	0	0	0	0
PCP, n/N (%), [events/100 pt-y]	0	0	0	0
Hepatitis B, n/N (%) [events/100 pt-y]	0	0	0	0
Hepatitis C, n/N (%) [events/100 pt-y]	0	0	0	0
Overall treatment-emergent ISRs^d	62 (42.2)	40 (20.8)	37 (20.3)	3 (1.7)
Malignancy, n (%) [events/100 pt-y]	2 (1.4) [0.53]	0	2 (1.1) [1.25]	2 (1.1) [1.41]
Other safety	4 (2.7)	0	0	0
IP, n/N (%) [events/100 pt-y]	4 (2.7) [1.07]	0	0	0
Demyelinating disorders, n/N (%) [events/100 pt-y]	0	0	0	0

ETN etanercept; BIW twice weekly; Pt-y patient years; MTX methotrexate; TEAE treatment-emergent adverse event; SAE serious adverse event; TB tuberculosis; PCP pneumocystis pneumonia; ISR injection site reaction; IP interstitial pneumonia.

^aMedical Dictionary for Regulatory Activities version 13.0; ^bExcluding infections and ISRs; ^c102 patients received placebo or ETN 10-mg BIW for 12 weeks in the bridging study, then ETN 25-mg BIW after moving to the long-term study until initial drug approval in Japan; ^dInjection site reactions includes erythema, hematoma, pain, hemorrhage, pruritus, rash, and warmth.

Table 3. (b) Common adverse events (AEs).

	Pooled (bridging, long-term, and self-injection) studies^a		Radiographic study^a
Treatment group No. of patients Estimate exposure	ETN 25-mg BIW N = 147 Total exposure = 375.4 pt-y		ETN 10-mg BIW n = 192 Total exposure = 168.3 pt-y		ETN 25-mg BIW n = 182 Total exposure = 160.3 pt-y		MTX ≤ 8 mg/wk n = 176 Total exposure = 141.6 pt-y
AE	n (%)	Events/100 pt-y	n (%)	Events/100 pt-y	n (%)	Events/100 pt-y	n (%)	Events/100 pt-y)
Rash	38 (25.9)	66 (17.58)	10 (5.2)	11 (6.536)	10 (5.5)	13 (8.110)	8 (4.5)	9 (6.357)
Eczema	27 (18.4)	49 (13.05)	7 (3.6)	8 (4.754)	8 (4.4)	10 (6.239)	8 (4.5)	9 (6.357)
Headache	32 (21.8)	48 (12.79)	5 (2.6)	5 (2.971)	9 (4.9)	15 (9.358)	4 (2.3)	5 (3.532)
Diarrhea	25 (17.0)	42 (11.19)	5 (2.6)	8 (4.754)	10 (5.5)	11 (6.862)	5 (2.8)	6 (4.238)
Pyrexia	18 (12.2)	45 (11.99)	2 (1.0)	3 (1.783)	9 (4.9)	11 (6.862)	6 (3.4)	7 (4.944)
Dizziness	25 (17.0)	37 (9.86)	7 (3.6)	7 (4.159)	3 (1.6)	4 (2.495)	1 (0.6)	1 (0.706)
Contusion	27 (18.4)	35 (9.32)	4 (2.1)	4 (2.377)	8 (4.4)	8 (4.991)	4 (2.3)	5 (3.532)
Pruritus	22 (15.0)	34 (9.06)	12 (6.3)	13 (7.724)	5 (2.7)	6 (3.743)	3 (1.7)	4 (2.825)
Nausea	18 (12.2)	27 (7.19)	4 (2.1)	4 (2.377)	1 (0.5)	1 (0.624)	7 (4.0)	8 (5.651)
Insomnia	19 (12.9)	24 (6.39)	9 (4.7)	9 (5.348)	2 (1.1)	2 (1.248)	9 (5.1)	9 (6.357)
Alanine aminotransferase increased	15 (10.2)	23 (6.13)	12 (6.3)	15 (8.913)	10 (5.5)	13 (8.110)	22 (12.5)	34 (24.015)
Cough	17 (11.6)	23 (6.13)	4 (2.1)	8 (4.754)	6 (3.3)	7 (4.367)	0	0
Vomiting	15 (10.2)	20 (5.33)	3 (1.6)	3 (1.783)	4 (2.2)	4 (2.495)	1 (0.6)	2 (1.413)
White blood cells urine positive	18 (12.2)	20 (5.33)	–	–	–	–	–	–
Injection site hemorrhage	15 (10.2)	21 (5.59)	2 (1.0)	4 (2.377)	2 (1.1)	2 (1.248)	0	0
Constipation	14 (9.5)	18 (4.80)	6 (3.1)	7 (4.159)	7 (3.8)	7 (4.367)	9 (5.1)	9 (6.357)
Stomatitis	13 (8.8)	18 (4.80)	8 (4.2)	8 (4.754)	3 (1.6)	3 (1.872)	8 (4.5)	12 (8.476)
Abdominal pain upper	15 (10.2)	17 (4.53)	3 (1.6)	3 (1.783)	3 (1.6)	3 (1.872)	5 (2.8)	5 (3.532)
Aspartate aminotransferase increased	9 (6.1)	16 (4.26)	8 (4.2)	11 (6.536)	8 (4.4)	11 (6.862)	18 (10.2)	25 (17.658)
Rhinitis allergic	9 (6.1)	10 (2.66)	6 (3.1)	6 (3.565)	1 (0.5)	1 (0.624)	3 (1.7)	4 (2.825)
Gastritis	8 (5.4)	8 (2.13)	3 (1.6)	3 (1.783)	1 (0.5)	1 (0.624)	6 (3.4)	8 (5.651)
Arthralgia	5 (3.4)	5 (1.33)	2 (1.0)	3 (1.783)	1 (0.5)	1 (0.624)	7 (4.0)	7 (4.944)
Abdominal discomfort	3 (2.0)	4 (1.07)	6 (3.1)	6 (3.565)	0	0	4 (2.3)	6 (4.238)
Transaminases increased	0	0	5 (2.6)	7 (4.159)	5 (2.7)	6 (3.743)	8 (4.5)	11 (7.770)
Hepatic function abnormal	0	0	5 (2.6)	5 (2.971)	3 (1.6)	4 (2.495)	6 (3.4)	9 (6.357)

ENT etanercept; BIW twice weekly; Pt-y patient years; MTX methotrexate.

^aMedical Dictionary for Regulatory Activities version 13.0.

Table 3. (c) Common infections.

	Pooled (bridging study, long-term, self-injection) studies^a		Radiographic study^a
Treatment group No. of patients Estimate exposure	ETN 25-mg BIW N = 147 Total exposure = 375.4 pt-y		ETN 10-mg BIW n = 192 Total exposure = 168.3 pt-y		ETN 25-mg BIW n = 182 Total exposure = 160.3 pt-y		MTX ≤ 8 mg/wk n = 176 Total exposure = 141.6 pt-y
Type of infection	n (%)	Events/100 pt-y	n (%)	Events/100 pt-y	n (%)	Events/100 pt-y	n (%)	Events/100 pt-y
Nasopharyngitis	100 (68.0)	424 (113.0)	45 (23.4)	69 (41.0)	37 (20.3)	50 (31.2)	43 (24.4)	58 (41.0)
Upper respiratory tract infection	36 (24.5)	86 (22.9)	20 (10.4)	30 (17.83)	21 (11.5)	31 (19.3)	20 (11.4)	29 (20.4)
Cystitis	15 (10.2)	35 (9.3)	4 (2.1)	8 (4.8)	9 (4.9)	12 (7.5)	6 (3.4)	6 (4.2)
Pharyngitis	15 (10.2)	20 (5.3)	18 (9.4)	27 (16.0)	15 (8.2)	21 (13.1)	12 (6.8)	17 (12.0)
Periodontitis	11 (7.5)	18 (4.8)	1 (0.5)	1 (0.6)	5 (2.7)	5 (3.2)	0	0
Conjunctivitis infective	5 (3.4)	13 (3.5)	0	0	0	0	0	0
Bronchitis	11 (7.5)	12 (3.2)	5 (2.6)	6 (3.6)	6 (3.3)	6 (3.7)	5 (2.8)	7 (4.9)
Herpes zoster	11 (7.5)	11 (2.9)	3 (1.6)	3 (1.8)	3 (1.6)	4 (2.5)	1 (0.6)	1 (0.7)
Tinea blanca	11 (7.5)	11 (2.9)	0	0	0	0	0	0
Gastroenteritis	10 (6.8)	10 (2.7)	1 (0.5)	1 (0.6)	1 (0.5)	1 (0.6)	5 (2.8)	5 (3.5)
Dental caries	9 (6.1)	9 (2.4)	4 (2.1)	4 (2.4)	8 (4.4)	10 (6.2)	3 (1.7)	3 (2.1)
Influenza	7 (4.8)	9 (2.4)	4 (2.1)	4 (2.4)	1 (0.5)	1 (0.6)	6 (3.4)	6 (4.2)
Oral herpes	8 (5.4)	8 (2.1)	6 (3.1)	6 (3.6)	2 (1.1)	2 (1.2)	2 (1.1)	2 (1.4)
Nail infection	7 (4.8)	8 (2.1)	1 (0.5)	1 (0.6)	0	0	1 (0.6)	1 (0.7)
Hordeolum	5 (3.4)	7 (1.9)	2 (1.0)	2 (1.2)	4 (2.2)	4 (2.5)	1 (0.6)	1 (0.7)
Pneumonia	6 (4.1)	6 (1.6)	6 (3.1)	6 (3.6)	2 (1.1)	2 (1.2)	0	0
Herpes virus infection	5 (3.4)	6 (1.6)	1 (0.5)	1 (0.6)	0	0	0	0
Tinea pedis	6 (4.1)	6 (1.6)	1 (0.5)	1 (0.6)	0	0	0	0
Sinusitis	5 (3.4)	5 (1.3)	2 (1.0)	2 (1.2)	1 (0.5)	1 (0.6)	0	0
Onychomycosis	5 (3.4)	5 (1.3)	1 (0.5)	1 (0.6)	0	0	0	0
Gastroenteritis viral	3 (2.0)	4 (1.1)	0	0	0	0	0	0
Herpes simplex	2 (1.4)	4 (1.1)	0	0	0	0	0	0
Arthritis bacterial	3 (2.0)	4 (1.1)	0	0	0	0	0	0
Cough	4 (2.7)	4 (1.1)	1 (0.5)	1 (0.6)	0	0	0	0
Urinary tract infection	3 (2.0)	3 (0.8)	1 (0.5)	2 (1.2)	0	0	0	0
Cellulitis	2 (1.4)	2 (0.5)	3 (1.6)	3 (1.8)	1 (0.5)	3 (1.9)	0	0
Pyelonephritis	2 (1.4)	2 (0.5)	1 (0.5)	3 (1.8)	0	0	1 (0.6)	1 (0.7)
Tonsillitis	1 (0.7)	1 (0.3)	0	0	1 (0.5)	1 (0.6)	2 (1.1)	2 (1.4)
Paronychia	0	0	1 (0.5)	1 (0.6)	3 (1.6)	3 (1.8)	1 (0.6)	1 (0.7)
Conjunctivitis	0	0	0	0	3 (1.6)	3 (1.8)	0	0
Gingivitis	0	0	1 (0.5)	1 (0.6)	2 (1.1)	2 (1.2)	2 (1.1)	2 (1.4)
Tinea infection	0	0	1 (0.5)	1 (0.6)	2 (1.1)	2 (1.2)	2 (1.1)	2 (1.4)
Candidiasis	0	0	0	0	1 (0.5)	2 (1.2)	0	0
Helicobacter infection	0	0	0	0	2 (1.1)	2 (1.2)	0	0
Pulpitis dental	0	0	0	0	1 (0.5)	1 (0.6)	2 (1.1)	2 (1.4)
Otitis media	0	0	4 (2.1)	4 (2.4)	0	0	1 (0.6)	1 (0.7)
Enterocolitis infectious	0	0	2 (1.0)	2 (1.2)	0	0	0	0
Sinobronchitis	0	0	1 (0.5)	2 (1.2)	0	0	0	0
Urethritis trichomonal	0	0	1 (0.5)	2 (1.2)	0	0	0	0
Streptococcal infection	0	0	0	0	0	0	2 (1.1)	3 (2.1)
Appendicitis	0	0	0	0	0	0	1 (0.6)	2 (1.4)

Pt-y patient-years.

^aMedical Dictionary for Regulatory Activities version 13.0.

Takeuchi T, Miyasaka N, Zang C, Alvarez D, Fletcher T, Wajdula J, et al. A phase 3 randomized, double-blind, multicenter comparative study evaluating the effect of etanercept versus methotrexate on radiographic outcomes, disease activity, and safety in Japanese subjects with active rheumatoid arthritis. Mod Rheumatol. 2013;23(4): 623–33.

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